tbuckley/cabot-search huggingface dataset:
HECTD1‐Mediated Ubiquitination and Degradation of Rubicon Regulates Autophagy and Osteoarthritis Pathogenesis
Authors: Shiyao Liao, Qiangqiang Zheng, Haotian Shen, Guang Yang, Yuzi Xu, Xiaolei Zhang, Hongwei Ouyang, Zongyou Pan
Journal: Arthritis & Rheumatology (2022)

Osteoarthritis (OA) is one of the most common degenerative joint diseases and is associated with autophagy suppression. However, the molecular mechanism of autophagy regulation in the context of OA is not fully understood. In this study, we sought to determine the role that HECTD1 plays in the pathogenesis of OA.We used RNA sequencing analysis to explore the differential expression of E3 ubiquitin ligase genes in healthy human cartilage and human cartilage affected by OA. Using surgery- and aging-induced OA mouse models, we comprehensively analyzed the function of the screened gene Hectd1 in the development of OA; furthermore, we dissected the mechanism by which HECTD1 regulates autophagy and OA progression using a combination of molecular biologic, cell biologic, and biochemical approaches.HECTD1 was significantly down-regulated in human OA cartilage samples compared to healthy cartilage samples. Overexpression of HECTD1 in mouse joints alleviated OA pathogenesis, whereas conditional depletion of Hectd1 in cartilage samples aggravated surgery- and aging-induced OA pathogenesis. Mechanistically, HECTD1 bound to Rubicon and ubiquitinated Rubicon at lysine residue 534, which targets Rubicon for proteasomal degradation. More importantly, HECTD1-mediated Rubicon degradation regulated chondrocyte autophagy, leading to mitigation of stress-induced chondrocyte death and the subsequent progression of OA.HECTD1 plays a crucial role in the pathogenesis of OA, in that HECTD1 regulates chondrocyte autophagy by ubiquitinating and targeting Rubicon for proteasomal degradation.
Role of Human Mesenchymal Stem Cells and Derived Extracellular Vesicles in Reducing Sensory Neuron Hyperexcitability and Pain Behaviors in Murine Osteoarthritis
Authors: Minji Ai, William E. Hotham, Luke A. Pattison, Qingxi Ma, Frances M.D. Henson, Ewan St. John Smith
Journal: Arthritis & Rheumatology (2022)

Mesenchymal stem/stromal cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) have been reported to alleviate pain in patients with knee osteoarthritis (OA). We undertook this study to determine whether MSCs and/or MSC-EVs reduce OA pain through influencing sensory neuron excitability in OA joints.
Effectiveness of an Unsupervised Online Yoga Program on Pain and Function in People With Knee Osteoarthritis
Authors: Kim L. Bennell, Sarah Schwartz, Pek Ling Teo, Stephanie Hawkins, Dave Mackenzie, Fiona McManus, Karen E. Lamb, Alexander J. Kimp, Ben Metcalf, David J. Hunter, Rana S. Hinman
Journal: Annals of Internal Medicine (2022)

Background: Yoga is a mind–body exercise typically done in groups in person, but this delivery method can be inconvenient, inaccessible, and costly. Effective online programs may increase access to exercise for knee osteoarthritis. Objective: To evaluate the effectiveness of an unsupervised 12-week online yoga program. Design: Two-group superiority randomized trial. (Australian New Zealand Clinical Trials Registry: ACTRN12620000012976) Setting: Community. Participants: 212 adults with symptomatic knee osteoarthritis. Intervention: Both groups received online osteoarthritis information (control). The yoga group also received access to an unsupervised online yoga program delivered via prerecorded videos over 12 weeks (1 video per week, with each session to be performed 3 times per week), with optional continuation thereafter. Measurements: Primary outcomes were changes in knee pain during walking (0 to 10 on a numerical rating scale) and physical function (0 to 68 on the Western Ontario and McMaster Universities Osteoarthritis Index) at 12 weeks (primary time point) and 24 weeks, analyzed using mixed-effects linear regression models. Secondary outcomes were self-reported overall knee pain, stiffness, depression, anxiety, stress, global change, quality of life, self-efficacy, fear of movement, and balance confidence. Adverse events were also collected. Results: A total of 195 (92%) and 189 (89%) participants provided 12- and 24-week primary outcomes, respectively. Compared with control at 12 weeks, yoga improved function (between-group mean difference in change, −4.0 [95% CI, −6.8 to −1.3]) but not knee pain during walking (between-group mean difference in change, −0.6 [CI, −1.2 to 0.1]), with more yoga participants than control participants achieving the minimal clinically important difference (MCID) for both outcomes. At 12 weeks, knee stiffness, quality of life, and arthritis self-efficacy improved more with yoga than the control intervention. Benefits were not maintained at 24 weeks. Adverse events were minor. Limitation: Participants were unblinded. Conclusion: Compared with online education, an unsupervised online yoga program improved physical function but not knee pain at 12 weeks in people with knee osteoarthritis, although the improvement did not reach the MCID and was not sustained at 24 weeks. Primary Funding Source: National Health and Medical Research Council and Centres of Research Excellence.
Integrative Medicine for Pain Management in Oncology: Society for Integrative Oncology–ASCO Guideline
Authors: Jun J. Mao, Nofisat Ismaila, Ting Bao, Debra Barton, Eran Ben-Arye, Eric L. Garland, Heather Greenlee, Thomas Leblanc, Richard T. Lee, Ana Maria Lopez, Charles Loprinzi, Gary H. Lyman, Jodi MacLeod, Viraj A. Master, Kavitha Ramchandran, Lynne I. Wagner, Eleanor M. Walker, Deborah Watkins Bruner, Claudia M. Witt, Eduardo Bruera
Journal: Journal of Clinical Oncology (2022)

PURPOSE The aim of this joint guideline is to provide evidence-based recommendations to practicing physicians and other health care providers on integrative approaches to managing pain in patients with cancer. METHODS The Society for Integrative Oncology and ASCO convened an expert panel of integrative oncology, medical oncology, radiation oncology, surgical oncology, palliative oncology, social sciences, mind-body medicine, nursing, and patient advocacy representatives. The literature search included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2021. Outcomes of interest included pain intensity, symptom relief, and adverse events. Expert panel members used this evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 227 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS Among adult patients, acupuncture should be recommended for aromatase inhibitor–related joint pain. Acupuncture or reflexology or acupressure may be recommended for general cancer pain or musculoskeletal pain. Hypnosis may be recommended to patients who experience procedural pain. Massage may be recommended to patients experiencing pain during palliative or hospice care. These recommendations are based on an intermediate level of evidence, benefit outweighing risk, and with moderate strength of recommendation. The quality of evidence for other mind-body interventions or natural products for pain is either low or inconclusive. There is insufficient or inconclusive evidence to make recommendations for pediatric patients. More research is needed to better characterize the role of integrative medicine interventions in the care of patients with cancer. Additional information is available at https://integrativeonc.org/practice-guidelines/guidelines and www.asco.org/survivorship-guidelines .
Selpercatinib in Patients With <i>RET</i> Fusion–Positive Non–Small-Cell Lung Cancer: Updated Safety and Efficacy From the Registrational LIBRETTO-001 Phase I/II Trial
Authors: Alexander Drilon, Vivek Subbiah, Oliver Gautschi, Pascale Tomasini, Filippo de Braud, Benjamin J. Solomon, Daniel Shao-Weng Tan, Guzmán Alonso, Jürgen Wolf, Keunchil Park, Koichi Goto, Victoria Soldatenkova, Sylwia Szymczak, Scott S. Barker, Tarun Puri, Aimee Bence Lin, Herbert Loong, Benjamin Besse
Journal: Journal of Clinical Oncology (2022)

Selpercatinib, a first-in-class, highly selective, and potent CNS-active RET kinase inhibitor, is currently approved for the treatment of patients with
The Management of Major Depressive Disorder: Synopsis of the 2022 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline
Authors: John R. McQuaid, Andrew Buelt, Vincent Capaldi, Matthew Fuller, Fuad Issa, Adam Edward Lang, Charles Hoge, David W. Oslin, James Sall, Ilse R. Wiechers, Scott Williams
Journal: Annals of Internal Medicine (2022)

Description: In February 2022, the U.S. Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) approved a joint clinical practice guideline (CPG) for the management of major depressive disorder (MDD). This synopsis summarizes key recommendations. Methods: Senior leaders within the VA and the DoD assembled a team to update the 2016 CPG for the management of MDD that included clinical stakeholders and conformed to the National Academy of Medicine's tenets for trustworthy CPGs. The guideline panel developed key questions, systematically searched and evaluated the literature, created two 1-page algorithms, and distilled 36 recommendations for care using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Select recommendations that were identified by the authors to represent key changes from the prior CPG are presented in this synopsis. Recommendations: The scope of the CPG is diverse; however, this synopsis focuses on key recommendations that the authors identified as important new evidence and changes to prior recommendations on pharmacologic management, pharmacogenomics, psychotherapy, complementary and alternative therapies, and the use of telemedicine.
Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signaling in cutaneous T-cell lymphoma
Authors: Maria Gluud, Emil M. H. Pallesen, Terkild B. Buus, Lise Mette Rahbek Gjerdrum, Lise M. Lindahl, Maria R. Kamstrup, Michael Bzorek, Maria Danielsen, Rikke Bech, Madalena N. Monteiro, Edda Blümel, Andreas Willerslev-Olsen, Anders Lykkebo-Valløe, Chella Krishna Vadivel, Thorbjørn Krejsgaard, Charlotte Menne Bonefeld, Carsten Geisler, Jürgen C. Becker, Sergei B. Koralov, Lars Iversen, Thomas Litman, Anders Woetmann, Niels Ødum
Journal: Blood (2022)

Abstract Cutaneous T-cell lymphoma (CTCL) is a devastating lymphoid malignancy characterized by the accumulation of malignant T cells in the dermis and epidermis. Skin lesions cause serious symptoms that hamper quality of life and are entry sites for bacterial infection, a major cause of morbidity and mortality in advanced diseases. The mechanism driving the pathological processes that compromise the skin barrier remains unknown. Here, we report increased transepidermal water loss and compromised expression of the skin barrier proteins filaggrin and filaggrin-2 in areas adjacent to TOX-positive T cells in CTCL skin lesions. Malignant T cells secrete mediators (including cytokines such as interleukin 13 [IL-13], IL-22, and oncostatin M) that activate STAT3 signaling and downregulate filaggrin and filaggrin-2 expression in human keratinocytes and reconstructed human epithelium. Consequently, the repression of filaggrins can be counteracted by a cocktail of antibodies targeting these cytokines/receptors, small interfering RNA–mediated knockdown of JAK1/STAT3, and JAK1 inhibitors. Notably, we show that treatment with a clinically approved JAK inhibitor, tofacitinib, increases filaggrin expression in lesional skin from patients with mycosis fungoides. Taken together, these findings indicate that malignant T cells secrete cytokines that induce skin barrier defects via a JAK1/STAT3-dependent mechanism. As clinical grade JAK inhibitors largely abrogate the negative effect of malignant T cells on skin barrier proteins, our findings suggest that such inhibitors provide novel treatment options for patients with CTCL with advanced disease and a compromised skin barrier.
Soft skin-interfaced mechano-acoustic sensors for real-time monitoring and patient feedback on respiratory and swallowing biomechanics
Authors: Youn J. Kang, Hany M. Arafa, Jae-Young Yoo, Cagla Kantarcigil, Jin-Tae Kim, Hyoyoung Jeong, Seonggwang Yoo, Seyong Oh, Joohee Kim, Changsheng Wu, Andreas Tzavelis, Yunyun Wu, Kyeongha Kwon, Joshua Winograd, Shuai Xu, Bonnie Martin-Harris, John A. Rogers
Journal: npj Digital Medicine (2022)

Swallowing is a complex neuromuscular activity regulated by the autonomic nervous system. Millions of adults suffer from dysphagia (impaired or difficulty swallowing), including patients with neurological disorders, head and neck cancer, gastrointestinal diseases, and respiratory disorders. Therapeutic treatments for dysphagia include interventions by speech-language pathologists designed to improve the physiology of the swallowing mechanism by training patients to initiate swallows with sufficient frequency and during the expiratory phase of the breathing cycle. These therapeutic treatments require bulky, expensive equipment to synchronously record swallows and respirations, confined to use in clinical settings. This paper introduces a wireless, wearable technology that enables continuous, mechanoacoustic tracking of respiratory activities and swallows through movements and vibratory processes monitored at the skin surface. Validation studies in healthy adults (n = 67) and patients with dysphagia (n = 4) establish measurement equivalency to existing clinical standard equipment. Additional studies using a differential mode of operation reveal similar performance even during routine daily activities and vigorous exercise. A graphical user interface with real-time data analytics and a separate, optional wireless module support both visual and haptic forms of feedback to facilitate the treatment of patients with dysphagia.
Corticotropin-Releasing Hormone Stimulation Following Low-Dose Dexamethasone Administration
Authors: Jack A. Yanovski
Journal: JAMA (1993)

<h3>Objective.</h3> —The biochemical and phenotypic presentation of mild hypercortisolism in Cushing's syndrome is often indistinguishable from that seen in pseudo-Cushing's states such as depression. Both dexamethasone suppression and corticotropin-releasing hormone (CRH) stimulation tests have been used individually to distinguish these conditions, but neither approach has achieved a diagnostic accuracy greater than 85%. Therefore, we sought to develop a combined dexamethasone-CRH test that would take advantage of the altered sensitivity of patients with Cushing's syndrome to both dexamethasone and CRH and would achieve greater accuracy in the diagnosis of Cushing's syndrome. <h3>Design.</h3> —Prospective cohort study. <h3>Setting.</h3> —Tertiary care research hospital. <h3>Patients.</h3> —A total of 58 adults referred for evaluation of mild hypercortisolism (urine free cortisol level &lt;1000 nmol/d). The diagnosis of Cushing's syndrome was confirmed at surgery in 39 patients. The diagnosis of a pseudo-Cushing's state was made in 19 patients on the basis of extended follow-up (mean, 28 months) without progression of cushingoid features. <h3>Intervention.</h3> —The low-dose dexamethasone suppression test, the CRH stimulation test, and the CRH stimulation test started 2 hours after completion of low-dose dexamethasone suppression (the dexamethasone-CRH test) were performed in all patients. <h3>Main Outcome Measures.</h3> —Sensitivity, specificity, and accuracy of the three procedures for diagnosis of Cushing's syndrome were calculated from plasma corticotropin, plasma cortisol, urine free cortisol, and urine 17-hydroxycorticosteroid values. <h3>Results.</h3> —The low-dose dexamethasone suppression test had 74% specificity, 69% sensitivity, and 71% diagnostic accuracy, using the standard criterion (17-hydroxycorticosteroid excretion level &gt;11.0 μmol/d on the second day of dexamethasone administration). With a urine free cortisol criterion for Cushing's syndrome of greater than 100 nmol/d, the low-dose dexamethasone suppression test had 100% specificity, 56% sensitivity, and 71% diagnostic accuracy. The CRH stimulation test without dexamethasone pretreatment had 100% specificity, 64% sensitivity, and 76% diagnostic accuracy. The diagnostic accuracy of the dexamethasone-CRH test for Cushing's syndrome was significantly greater than the accuracy of either the low-dose dexamethasone test or the CRH test alone (<i>P</i>&lt;.01). A plasma cortisol concentration greater than 38 nmol/L measured 15 minutes after the administration of CRH correctly identified all cases of Cushing's syndrome and all cases of pseudo-Cushing's states (100% specificity, sensitivity, and diagnostic accuracy). <h3>Conclusion.</h3> —The dexamethasone-CRH test is a more accurate test to distinguish Cushing's syndrome from pseudo-Cushing's states in patients with mild hypercortisolism. (<i>JAMA</i>. 1993;269:2232-2238)
Tumor oxygenation nanoliposome synergistic hypoxia-inducible-factor-1 inhibitor enhanced Iodine-125 seed brachytherapy for esophageal cancer
Authors: Xijuan Yao, Shuting Lu, Cheng Feng, Ruiyang Suo, Hang Li, Yi Zhang, Qi Chen, Jian Lu, Bo Wu, Jinhe Guo
Journal: Biomaterials (2022)
Transferrin-guided intelligent nanovesicles augment the targetability and potency of clinical PLK1 inhibitor to acute myeloid leukemia
Authors: Yifeng Xia, Jingnan An, Jiaying Li, Wenxing Gu, Yifan Zhang, Songsong Zhao, Cenzhu Zhao, Yang Xu, Bin Li, Zhiyuan Zhong, Fenghua Meng
Journal: Bioactive Materials (2022)

Acute myeloid leukemia (AML) remains a most lethal hematological malignancy, partly because of its slow development of targeted therapies compared with other cancers. PLK1 inhibitor, volasertib (Vol), is among the few molecular targeted drugs granted breakthrough therapy status for AML; however, its fast clearance and dose-limiting toxicity greatly restrain its clinical benefits. Here, we report that transferrin-guided polymersomes (TPs) markedly augment the targetability, potency and safety of Vol to AML. Vol-loaded TPs (TPVol) with 4% transferrin exhibited best cellular uptake, effective down-regulation of p-PLK1, p-PTEN and p-AKT and superior apoptotic activity to free Vol in MV-4-11 leukemic cells. Intravenous injection of TPVol gave 6-fold higher AUC than free Vol and notable accumulation in AML-residing bone marrow. The efficacy studies in orthotopic MV-4-11 leukemic model demonstrated that TPVol significantly reduced leukemic cell proportions in periphery blood, bone marrow, liver and spleen, effectively enhanced mouse survival rate, and impeded bone loss. This transferrin-guided nano-delivery of molecular targeted drugs appears to be an interesting strategy towards the development of novel treatments for AML.
EGFR, the Lazarus target for precision oncology in glioblastoma
Authors: Benjamin Lin, Julia Ziebro, Erin Smithberger, Kasey R Skinner, Eva Zhao, Timothy F Cloughesy, Zev A Binder, Donald M O’Rourke, David A Nathanson, Frank B Furnari, C Ryan Miller
Journal: Neuro-Oncology (2022)

Abstract The Lazarus effect is a rare condition that happens when someone seemingly dead shows signs of life. The epidermal growth factor receptor (EGFR) represents a target in the fatal neoplasm glioblastoma (GBM) that through a series of negative clinical trials has prompted a vocal subset of the neuro-oncology community to declare this target dead. However, an argument can be made that the core tenets of precision oncology were overlooked in the initial clinical enthusiasm over EGFR as a therapeutic target in GBM. Namely, the wrong drugs were tested on the wrong patients at the wrong time. Furthermore, new insights into the biology of EGFR in GBM vis-à-vis other EGFR-driven neoplasms, such as non-small cell lung cancer, and development of novel GBM-specific EGFR therapeutics resurrects this target for future studies. Here, we will examine the distinct EGFR biology in GBM, how it exacerbates the challenge of treating a CNS neoplasm, how these unique challenges have influenced past and present EGFR-targeted therapeutic design and clinical trials, and what adjustments are needed to therapeutically exploit EGFR in this devastating disease.
Domain generalization for prostate segmentation in transrectal ultrasound images: A multi-center study
Authors: Sulaiman Vesal, Iani Gayo, Indrani Bhattacharya, Shyam Natarajan, Leonard S. Marks, Dean C Barratt, Richard E. Fan, Yipeng Hu, Geoffrey A. Sonn, Mirabela Rusu
Journal: Medical Image Analysis (2022)
Cardio-Oncology in Portugal
Authors: Vera Vaz Ferreira, Isabel Cardoso, Inês Ângelo, Joana Feliciano, Tânia Branco Mano, Sílvia Aguiar Rosa, Luís Almeida-Morais, Luísa Moura Branco, Boban Thomas, Rui Cruz Ferreira
Journal: JACC CardioOncology (2022)
Involvement of Rho-Associated Coiled-Coil Containing Kinase (ROCK) in BCR-ABL1 Tyrosine Kinase Inhibitor Cardiovascular Toxicity
Authors: Brian Yu, Afaf E.G. Osman, Nikola Sladojevic, Nicole Prabhu, Haw-Chih Tai, Daiqing Chen, Gerardo Perla, Linus Park, Richard A. Larson, James K. Liao
Journal: JACC CardioOncology (2022)

Second- and third-generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) are associated with cardiovascular adverse events (CVAEs) in patients with Philadelphia chromosome–positive (Ph+) leukemia. We hypothesized that second- and third-generation BCR-ABL1 TKIs may cause CVAEs through the activation of Rho-associated coiled-coil containing kinase (ROCK). Peripheral blood mononuclear cells from 53 Ph+ patients on TKIs and 15 control patients without Ph+ leukemia were assessed for ROCK activity through capillary electrophoresis (median follow-up = 26 months [Q1-Q3: 5-37 months]). We also investigated the effects of TKIs and ROCK on endothelial dysfunction in vitro, which could contribute to CVAEs. Patients receiving second- and third-generation TKIs had 1.6-fold greater ROCK activity compared with patients receiving imatinib and control patients. Elevated ROCK activity was associated with an increased incidence of CVAEs in Ph+ leukemia patients. In endothelial cells in vitro, we found that dasatinib and ponatinib treatment led to changes in actin intensity and endothelial permeability, which can be reversed by pharmacologic inhibition of ROCK. Ponatinib led to decreased cell proliferation, but this was not accompanied by senescence. Dasatinib and ponatinib treatment led to phosphor-inhibition of endothelial nitric oxide synthase and decreased nitric oxide production. ROCK inhibition reversed endothelial permeability and endothelial nitric oxide synthase–related endothelial dysfunction. Imatinib and nilotinib induce phosphorylation of p190RhoGAP. Our findings suggest ROCK activity may be a prognostic indicator of CVAEs in patients receiving BCR-ABL1 TKIs. With further study, ROCK inhibition may be a promising approach to reduce the incidence of CVAEs associated with second- and third-generation BCR-ABL1 TKIs.
How to Manage Cisplatin-Based Chemotherapy–Related Cardiovascular Disease in Patients With Testicular Cancer
Authors: Sindhuja Kadambi, Suparna C. Clasen, Chunkit Fung
Journal: JACC CardioOncology (2022)

• Patients with advanced testicular cancer receive cisplatin-based chemotherapy with a high rate of cure. • Cisplatin-based chemotherapy increases risks of acute vascular complications among testicular cancer survivors. • Cisplatin-based chemotherapy increases cardiovascular disease risk factors and cardiovascular disease among testicular cancer survivors. • Long-term management of cardiovascular risk factors and cardiovascular disease in testicular cancer survivors is recommended.